Unit 3: Myeloproliferative Disorders Flashcards
MPNs =
monoclonal hyperproliferation abnormalities
(neoplasms) or myeloproliferative neoplasms.
MPNs aka…
chronic non-lymphoid “malignancies”.
MPNs usually affects what precursors?
erythroid, granulocyte, monocyte, or megakaryocyte precursors
-All can vary dramatically in presentation.
MPNs:
All present as stable ___________ disorders, which can have ______ phases.
chronic, acute
Can more than one MPN coexist?
-All can coexist with each other. (You can have > 1 at the same time!)
-All can transform into each other.
-All can transform into AML (& very rarely, even into ALL)!
MPN can exhibit hyper___________ and or hyper___________.
hypereosinophilia or hyperbasophilia
Ture or false:
MPN can have problems with thrombosis or hemorrhage.
True
Why have MPNs been hard to classify?
due to overlapping characteristics
MPNs are ________ in origin from a single pluripotential
hemopoietic stem cell.
Clonal
Major defect with Polycythemia Vera (PV)?
overproduction of RBCs
Major defect with Chronic Myelocytic Leukemia (CML)?
overproduction of granulocytes
Major defect with Essential Thrombocytosis (ET)?
overproduction of platelets
Major defect with Myelofibrosis (PMF)?
overproduction of bone marrow fibroblasts
Etiology of Polycythemia Vera (PV)?
Clonal stem cell disorder (various mutations)
Causes unregulated proliferation of bone marrow erythroid, granulocytic, and megakaryocytic elements with ever-increasing RBC #s in p.b.
Polycythemia Vera (PV)
How to cells appear and function with Polycythemia Vera?
-all cells appear normal
-RBCs function normally, have N. lifespan.
-RBCs are normo- normo-….until Fe stores get used up.
Polycythemia Vera:
Best know mutation is in gene for protein called ____
(>90% of patients).
JAK2
JAK2 is a…
nonreceptor tyrosine kinase
It plays an important role for the EPO & TPO receptors up to their place on the RBC’s surface, so these cells are super sensitive!
JAK2 protein
Even though hyperactivity of JAK2 may not initiate PV, it is…
associated with PV.
Stem cells with JAK2 mutation are resistant to…
erythropoietin apoptosis
_____ mutation also associated with ET & CIMF.
JAK2
What are the two major criteria that both need to be met for Diagnosis of PV?
- Hgb level of:
>18.5 g/dL in men
>16.5 g/dL in women - Identification of JAK2 mutation
What are the 3 minor criterion for PV diagnosis? (only one needs to to be met along with the two major)
- panmyelosis in bone marrow
- low serum EPO level*
- autonomous, erythoid colony formation
What are the clinical symptoms of PV?
“Ruddy” face
Itchy skin
Hypertension
Vertigo
Feeling of fullness after eating only small amounts
Blurred vision
Headaches
↑ [uric acid]
Splenomegaly
PV symptoms:
LAP is…
increased
PV symptoms:
serum B12?
oxygen saturation?
increased
normal
Clinical Symptoms of PV:
Why a ruddy face?
Severely ↑ RBCS show up as pink color under the skin
Clinical Symptoms of PV:
Why hypertension?
Severely ↑ RBCS cause “sludgy” blood
Clinical Symptoms of PV:
Why a feeling of fullness?
Splenomegaly pressure on stomach (from ↑ cell turnover)
Clinical Symptoms of PV:
Why increased uric acid?
↑ DNA degradation due to ↑ cell turnover
*** PV:
____ EPO levels
low
In all polycythemias: Absolute erythrocytosis, with:
RBC(T) =
6 - 10 x 10 6/uL
PV:
Hgb >
18 g/dL
PV:
Hct =
55 - 60%
PV:
ESR =
0 - 3 mm/hr
PV:
_________ WBCs and plts., with N. morphology
Normal or increased
-Immature granulocytes and nRBCs
Platelet range seen with Polycythemia Vera?
400,000 - 2,000,000/uL
PV:
plts with _____ forms and ___________ function.
giant, abnormal
PV:
Bone marrow is __________, with worsening fibrosis
hypercellular
PV:
What decreases when disease progresses from “stable phase” to “spent phase”?
Fe stores
What is the treatment for Polycythemia Vera?
No cure
Therapeutic phlebotomy 1st choice
Myelosuppressive drugs (Ex., hydroxyurea) can
↓ blood volume & ↑ Fe stores.
What is the risk of Myelosuppressive drug treatment with Polycythemia Vera?
later risk of transformation into AML. (About 15% all PV pts. progress into AML eventually, anyway)
Clonal stem cell disorder
Causes extreme elevation of both mature & immature myeloid cells in bone marrow.. which then shows up in the p.b.
Slow clinical course
Primarily seen in adults, but can occur at any age
Chronic Myelocytic / Myelogenous / Myeloid Leukemia (CML)
CML clinical symptoms?
Anemia
Fever
Excessive bleeding or bruising
Malaise
Hepatosplenomegaly
Hepatosplenomegaly causes what to happen to the patient?
A feeling of fullness and eventual weight loss
CML:
> 95% pts. are ____________ chromosome +
Philadelphia (Ph’) ***
(unequal but reciprocal translocation of chromosomes 9 and 22)
What is the prognosis for CML Ph’ pts.?
Good prognosis
This translocation puts the c-ABL oncogene next to the
BCR (Breakpoint Cluster Region) gene. (There also can be additional large deletions on either side of this breakpoint.)
t (9,22), Philadelphia (Ph’) chromosome
t (9,22) happens in what cells?
Translocation occurs in granulocytes, RBCs, mega-
karyocytes & lymphs.
CML with t (9,22):
This translocation puts the c-ABL oncogene next to the
BCR (Breakpoint Cluster Region) gene. (There also can be additional large deletions on either side of this breakpoint.)
The product is a ____________ protein, enhances tyrosine kinase activity – 98% of pts. are
BCR / ABL +
BCR/ABL fusion***
– 98% of pts. are BCR / ABL +
Why do cells with the t (9,22) defect accumulate even more defects?
Cells with this defect are hyperproliferative, AND
genetically unstable
Ph’ and BCR/ABL protein can be diagnosed by…
-karyotyping (chromosomal level)
-FISH (cellular level)
-PCR (molecular level)
What gene deletion can also occur in CML? What is the prognosis?
9q34 deletion in the argininosuccinate
synthetase gene
bad prognosis
CML is “When the p.b. looks like…
bone marrow***
THE HIGHEST WBC COUNTS IN ALL LEUKEMIAS COME
FROM _______!
CML***
CML:
WBCT >___________/uL, & usually _____________/uL (!) with neutrophilia, basophilia, eosinophilia and often thrombocytosis.
100,000
200,000 - 500,000/
CML shows a huge ______ shift with what developmental stages?***
left
all developmental stages
CML:
~ ___ % blasts & pros, ____% myelos, _____ % metas,
_____% segs
1-5
10-20
10-30
30-50
*Both basophilia & eosinophilia can be seen
CML:
> ___% basophilia heralds an impending blast crisis.
20*
CML:
LAP score is ________ in early stages.
decreased
(but N. or increased in all other MPNs.)
Plt. count with CML
often increased
-Pseudo-Pelger-Huet may be seen
CML:
Anemia, if present, is morphologically typically
…
normo-, normo-
What is the normal M:E ratio range in adults?
1.5:1 to 3.3:1
CML:
Bone marrow shows striking increase in M:E ratio (can range from _________, but with ____ % blasts.)
10:1 - 50:1
<30
Three phases of CML?
-chronic phase
-accelerated phase
-Blastic phase
Three phases of CML:
Usually occurs prior to blastic phase
Poor response to therapies
Increase in symptoms and lab values
accelerated phase
Three phases of CML:
Increased blast count to >20%
Becomes either AML, or more rarely, ALL.
Blastic phase
Previously the only cure for CML was BMT (performed while in chronic phase) now, what is the treatment?
Gleevec (imatinib mesylate) from Novartis Pharmaceuticals
About _____ CML pts. undergo “blast transformation” from chronic into acute phase.
¾
How does Gleevec work?
binds directly to the
BCR/ABL fusion
protein/tyrosine kinase produced by Ph’.
Decreasing # of GF receptors in the abnormal cells, Gleevec causes abnormal cells to die
As abnormal cells die, normal cells proliferate.
-And eventually no more abnormal, Ph translocation-
containing cells can be found = molecular remission
What is the “cure” rate of CML with Gleevec?
> 88% of pts. in chronic phase (with variable
results in other phases).
CML Treatment with Gleevec:
With effective therapy, the advent of monitoring for
_________________
has now become an important prognostic indicator.
Minimal Residual Disease*
In general poorer CML prognoses are associated with increased…
↑ WBCT (> 100,000/uL)
↑ basophilia
↑ blasts
-Presence of any other abnormal cytogenetics.
In general poorer CML prognosis with plt. counts that are…
very increased or very decreased (> 700,000/uL or
< 150,000/uL)
NOTE: Ph’ neg. CML is now considered to be _______.
CMML
Primary Myelofibrosis (PMF) aka…
Chronic Idiopathic Myelofibrosis (CIMF) and
Myelofibrosis with Myeloid Metaplasia, MMM!
Primary Myelofibrosis (PMF) is a clonal stem cell disorder (associated with _____
mutation – 65% of patients)
JAK2
Hyperproliferation of bone marrow fibroblasts (in response to neoplastic mutation elsewhere, that has caused the overproduction of GFs.)
Primary Myelofibrosis (PMF)
Primary Myelofibrosis (PMF) can convert into _____!
AML
Causes progressive bone marrow fibrosis (↑ collagen)
Produces extensive extramedullary hematopoiesis with massive hepatosplenomegaly
Primary Myelofibrosis (PMF)
Does Primary Myelofibrosis (PMF) cause splenomegaly?
massive hepatosplenomegaly!
Myelofibrosis Clinical Symptoms
Severe hepatosplenomegaly
Abdominal pain
Weight loss
Normo-, normo cells
-normal symptoms of anemia
Myelofibrosis is normo- normo anemia of normally sized & normally colored
RBCs, even though they may be…
teardrop-shaped, due
to the extramedullary hematopoiesis.
What are the usual symptoms of anemia?
Pallor, malaise, & dyspnea
Myelofibrosis Lab Findings:
Highly variable!
Characteristic: striking p.b. aniso/poik with teardrops/dacrocytes; why?***
Due to severe extra-
medullary hematopoiesis
Myelofibrosis Lab Findings:
Poik becomes more severe as disease progresses to…
bone marrow failure!***
Myelofibrosis Lab Findings:
______ shift & variably increased WBC count (_____________ uL, & doesn’t decrease with disease progression)
Left
15,000 - 30,000/
Myelofibrosis Lab Findings:
Characteristic - _______ due to varying degrees of bone marrow fibrosis.
dry tap
What three conditions characteristically have a dry tap?***
-PMF
-AMegL
-HCL
Myelofibrosis have _________ plt. counts.
variable
Myelofibrosis Treatment
Chemo.
Steroids
Splenectomy
Eventual bone marrow transplant
Myelofibrosis:
What are the two most common complications of total bone marrow failure that patients die from?
overwhelming infections & massive hemorrhage
Essential Thrombocythemia
(ET):
Clonal stem cell disorder (associated with ______ mutation)
JAK2
Essential Thrombocythemia
(ET):
causes extremley increased _______ count
plt.
Essential Thrombocythemia
(ET):
Plt. function is abnormal unless #s ↓ by
plateletpheresis – this differentiates it from what leukemia?
AML M7 - AMegL
ET Clinical Symptoms
Abdominal pain
Epistaxis
GI bleeding
AND:
Bleeding after minor dental surgery
Thrombotic events
What is the platelet count around with ET?
~ 600,000 -2,500,000/uL.
What kind of plts. are found with ET?
Giant, bizarre plts., but NOT
megakaryocyte fragments in p.b.
ET Lab Findings:
WBC findings?
plt. aggregation studies?
Slt. leukocytosis with neutrophilia
Abnormal plt. aggregation studies
Note: M7/Acute megakaryoblastic leukemia (AMKL) has ______ in p.b.
ET is NOT usually accompanied by ____ _.
nRBCs
Which is positive for giant plts.?
M7/Acute megakaryoblastic leukemia (AMKL) or ET?
Both
Left shift:
M7/Acute megakaryoblastic leukemia (AMKL)?
ET?
M7 = rare left shift
ET = slight left shift
megakaryocyte fragments:
M7/Acute megakaryoblastic leukemia (AMKL)?
ET?
M7 = positive
ET = no fragments
ET Treatment
Myelosuppressive drugs (Ex., hydroxyurea.)
IFN-α if myelosuppressives can’t be given
Plateletpheresis to reduce plt. mass
-Also restores normal plt function (for a while!)
What is the risk of treating ET with Myelosuppressive drugs (Ex., hydroxyurea.) ?
Incurs higher risk of transforming into AML later on.
The WHO breaks CML further into…
-Ph. chrom. - subtype
CNL (Chronic Neutrophilic Leukemia, has no metas or myelos)
CEL (Chronic Eosinophilic Leukemia)
MPN, Unclassified
WBC is typically _________x 10^3 uL with CML
> 100
Hgb (g/dL) is ___________ with PV.
greatly increased
Platelet count is _________ (x 10^3/uL) with PV.
> 1000
Bone marrow fibroblasts are ___________ with PMF.
moderately increased to marked increase
What is LAP score with early CML?
moderately decreased
What is Lap score with PV?
Increased
What is LAP score with PMF?
normal to increased
What is LAP score with ET?
normal to increased
Which Chronic Myeloproliferative disorder is associated with >95% Ph’ positive?
Which are negative?
CML
Negative for PV, PMF, and ET
